Manufacture of pyremdjine



Patented Apr. 20, 1954 UNITED STATES PATENT OFF-ICE MANUFACTURE OF PYRIMIDINE v DERIVATIVES Charles Henry Vasey, Blackley, Manchester, England, assignor to Imperial Chemical Industries Limited, a corporation of Great Britain No Drawing. Application March 31, 1952, Serial No. 279,687

Claims priority, application Great Britain April 6, 1951 4 Claims.

Thisinvention relates to improvements in the manufacture of pyrimidine derivatives which possess useful anti-convulsant properties. The

pyrimidine derivatives with which this invention is concerned are those ofthe formula C CH1 wherein R1, R2 and R3 have the meaning stated above and wherein R4 stands for an alkyl radical, an alkenyl radical or an aralkyl radical.

According to a further feature of the invention the said pyrimidine derivatives are manufactured by a process which comprises reducing compounds of the formula:

or their hydrates or salts wherein R1, R2 and R3 have the meaning stated above.

The starting materials are the subject of copending British application No. 8020/51 which corresponds to U. S. application Serial No.279,686, now U. S. Patent 2,666,056 of January 12, 1954, of even date herewith and may be obtained by processes described in that specification.

The processes of reduction of the present invention may be brought about by the conventional methods, for example by means of zinc and acetic acid; by means of boiling formic acid or formamide either alone or in a solvent for example dimethylformamide; by heating with a hydrogen-containing catalyst, for example W5 Raney nickel; by means of hydrogen in presence of a catalyst, for example Raney nickel or palladised strontium carbonate.

It is to be understood that when the compound to be reduced contains an unsaturated radical, for example a cyclohexenyl or alkenyl radical, which it is desired to retain in the final compound, the reduction process should be a mild one, as by means of boiling formic acid or of formamide. g

The invention is illustrated but not limited by the following examples in which the parts are by weight.

- Example 1 2 parts of 2-ethoxy-5-phenyl-5-ethylhexahy-- dropyrimidine-4z6-dione, in 250 parts of ethanol are stirred with 1 part of Raney nickel catalyst and hydrogen at 50 atmospheres pressure at 90 C. for 5 hours. The mixture is then cooled to C. and filtered. The filtrate is evaporated to small volume and cooled. '5-phenyl-5-ethylhexahydropyrimidine-4zfi-dione, M. P. 281 C.,'is fi1 tered off and dried. V

The same product is obtained when the starting material is 2-n-propoxy-, 2-isopropoxy-2-n-butoxy-, 2-sec.-butoxy-, 2-allyloxyand '2-benzyloxy-5-phenyl-5-ethylhexahydropyrimidine 4 6 diones.

Example 2 v 2 parts of 2-ethoxy-5-phenyl-5-ethylhexahydropyrimidine-izfi-dione are boiled under reflux with 50 parts of formamide for half an hour, The mixture is then cooled and filtered and-5 phenyl 5 ethylhexahydropyrimidine-4:fi-dione, M. P. 281 0., is obtained by crystallisation of th solid residue from ethanol. I

Example 3 3 parts of 2-ethoxy-5-phenyl-5-ethylhexahydropyrimidine-4:6 -dione are heated under reflux with 100 parts of 98% aqueous formic acid for 4 hours. Approximately parts of formic-acid are then distilled oii and the residue is cooled and filtered. 5-phenyl-5-ethylhexahydropyrimidine- 4:6-dione is obtained, M. P. 281' C.

Example 4 Example 5 2 parts of 5-phenyl-5-ethyltetrahydropyrimidine-4:6-dione and 250 parts of ethanol are boiled under reflux for 2 hours with 20 parts of hydrogen-containing Raney nickel (prepared by method W5 as described in J. A. C. 8., 1948, 70, 695). The mixture is then filtered and evaporated to small volume and cooled and again filtered. v

The solid residue consists of 5-phenyl-5-ethylhexahydropyrimidine-l:6-dione, M. P. 281 C.

Example 6 5 parts of zinc dust are added to a solution of 1 part of 2-ethoxy-S-phenyl5-ethylhexahydropyrimidine-4:6-dione in 30 parts of 50% aqueous acetic acid. 2 parts of concentrated hydrochloric acid are then added and the mixture is heated at 95l00 C. for 30 minutes, then allowed to cool to room temperature during 15 hours. It is then for 2 hours with 100 parts of ethanol and parts of hydrogen-containing (W5) Raney nickel (cf. J. A. C. 8., 70, 695 (1948)). Themixture is then filtered and the filtrate is evaporated to small volume and cooled and filtered. The solid residue consists of 5-phenyl-5-methylhexahydropyrimidine-4:6-dione, M. P. 296 0.

filtered and the solid residue is Washed with water and extracted with 50 parts of boiling 80% ethanol. The filtrate is cooled and filtered. The solid residue consists of 5-pheny1-5- ethylhexa-. hydropyrimidine-4:6-dione. M. P. 281 C.

Example 7 10 parts of 5-pheny1-5-ethyltetrahydropyrimidine-zG-dione, 2 parts of palladised strontium carbonate and 1000. parts of ethanol are stirred together at 90-160" C. in an atmosphereof hy drogen at a pressure of 108 atmos heres for 5 hours. The mixture is then filtered and the 111- trate is evaporated to small volume and cooled. 5 phenyl 5 ethylhexahydropyrimidine-4:6- d-ione, M. P. 281 C., is obtainedloy filtration.

Eazample 8 Example 9 1 part of 2-ethoxy-5-A -cyclohexeny1-5eethylhexahydropyrimidine-4:6-dione is boiled under reflux with 5 parts of formamide for 90 minutes. The mixture is then. cooled and filtered and the solid residue is crystallised from methanol to give 5-A -cyclohexenyl 5 ethylhexahydropyrimidine-4:6-dione, as a colourless solid, P. 2682C.

Example 10 1 part of 2-ethoxy-5-phenyl-5-methylhexahydropyrimidine-4:6-dione is boiled under reflux Example 11 A solution of 10 parts of 5-phenyl-5-ethyltetrahydropyrimidine 4:6 dione monohydrochloride in 200 parts of glacial acetic acid is shaken in an atmosphere of hydrogen with 1 part of Adams platinum' oxide catalyst at room temperature until .no further hydrogen is absorbed. The product is then heated to -100 C. and filtered. The filtrate is distilled under reduced pressure and the residue is crystallised from ethanol. 5 phenyl 5 ethylhexahydropyrimidine-4:6- dione, M. P. 281 0., is obtained. 7

The same product is obtained startmg; from 5 phenyl 5 ethyltetrah-ydropyrimidine 6: dione monohydrate. a

WhatIclaimis: 1 1

1. A rocess tor themanufacture o pyrimidine derivatives of the formula p R} 00 m; 7 V wherein R1 stands for a phenyl radical and R2 stands for an alkyl radical of not more than 3 carbon atoms which comprises reducing a com! pound of the formula 1 (1] 011033 R: GO-1YH wherein R1 and R2 have the meaning stated above and wherein R3 stands for a radical selected from the group consisting of alkyl and aralkyl radical.

2. Process as claimed in claim 1 wherein the reduction is brought about :by means of hydrogen in presence of a hydrogenation catalyst.

3. Process as claimed in claim 2 Wherei-n'the' hydrogenation catalyst is a finely divided metal selected from the group consisting of nickel, cohalt, platinum and palladium.

4. Process as claimed incla'im 1 wherein the reduction is brought about in the presence of boiling formamide; Y r 1 References Cited in the file of this patent B on. e al- Nov. 2'1 195.1 

1. A PROCESS FOR THE MANUFACTURE OF PYRIMIDINE DERIVATIVES OF THE FORMULA 